Molecular subtyping of brain metastases and implications for therapy

Abstract

Molecular subtyping of tumors and treatment with specifically targeted therapy is a rapidly developing trend in oncology. Genetic and protein biomarkers impact biological behavior, patient prognosis, and inform treatment options. Select examples include EGFR mutations in primary non-small cell lung cancers, Her2 overexpression in breast cancer, and BRAF mutations in melanoma. Systemic benefit is emphasized in targeted therapies; yet lung cancer, breast cancer, and melanoma comprise the most common diagnoses in patients with brain metastases making the effectiveness of targeted therapies in the treatment and/or prevention of brain metastases relevant.Emerging evidence suggests efficacy for targeted therapy in the setting of brain metastases. Randomized, phase III clinical trials indicate targeted HER2 treatment with lapatinib and capecitabine in brain metastases from breast cancer increases the time to progression and decreases the frequency of CNS involvement at progression. Phase II trials and retrospective reviews for gefitinib and erlotinib demonstrate these agents may have a role in both the chemoprevention of brain metastases and, in combination with WBRT, treatment for non-small cell lung cancer (NSCLC) brain metastases. Dabrafenib and other BRAF inhibitors have demonstrated improved survival in patients with brain metastases from melanoma in a recent phase II clinical trial. Further data that support the use of these agents are the subject of several active clinical trials. Challenges and future directions for targeted therapies in brain metastases include both better characterization and drug design with respect to central nervous system distribution. Limited published data demonstrate suboptimal CNS distribution of currently available targeted chemotherapeutic agents. Increasing systemic dosing, alternate delivery methods, and new compounds with improved CNS distribution are being pursued. Additionally, eventual resistance to targeted therapies poses a challenge; however, research is showing resistance mutations are conserved and relatively predictable creating opportunities for second-line therapies with additional targeted drugs. Newer targeted therapies represent an additional chemotherapeutic option for the treatment and/or prevention of brain metastases in patients with an appropriate molecular profile.